SPID#: 14 To better understand the contribution of chronic immune activation in progression of lentiviral-induced disease, we infected a total of 9 rhesus macaques with SIVmac251 and followed them for disease onset. At the time of virus infection and at monthly intervals thereafter, groups of 3 animals each were then given either placebo (group I), allogeneic cells (group II), or an alternate schedule of allogeneic cells, KLH, and tetanus toxoid (group III). A fourth group of 3 macaques (group IV, control) was given multiple antigens, similar to the procedures used for group III, but the macaques were not infected. All animals which were hyperactivated and infected with SIV (group III) died within 7 months (2 animals died in 4 months), while only one animal died in group I and II by 7 months. None of the animals in group IV died. The animals in group III which died by 4 months as well as those in group I and II never seroconverted and had high p24 antigenemia. Studies of immune activation showed that animals in group IV responded with increasing antibody titers to the soluble antigens (Tet Toxoid and KLH) while group II animals initially responded but lost specific antibody titers prior to death. All 5 animals which died of rapid death showed high levels of soluble TNFR-II in their sera. The data presented here suggest that hyperactivation of SIV-infected rhesus macaques can speed progression of disease. Such information may be useful in understanding the role of immune activation and the contribution of cytokines to the development of AIDS.